EP0300737A2 - Dérivés de gènes peptides de calcitonine apparentés - Google Patents

Dérivés de gènes peptides de calcitonine apparentés Download PDF

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Publication number
EP0300737A2
EP0300737A2 EP88306600A EP88306600A EP0300737A2 EP 0300737 A2 EP0300737 A2 EP 0300737A2 EP 88306600 A EP88306600 A EP 88306600A EP 88306600 A EP88306600 A EP 88306600A EP 0300737 A2 EP0300737 A2 EP 0300737A2
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EP
European Patent Office
Prior art keywords
peptide
group
asn
phe
gly
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Granted
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EP88306600A
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German (de)
English (en)
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EP0300737B1 (fr
EP0300737A3 (en
Inventor
Kaoru Morita
Toyonobu Uzawa
Masayuki Hori
Toshiharu Noda
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Asahi Kasei Corp
Original Assignee
Toyo Jozo KK
Asahi Kasei Kogyo KK
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Publication of EP0300737A3 publication Critical patent/EP0300737A3/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/57527—Calcitonin gene related peptide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates to novel human calcitonin gene related peptide (hereinafter designated as h-CGRP) derivatives, useful for the treatment of calcium metabolic disorders, cardiac disease and ulcers, and for the improvement of cerebral circulation.
  • h-CGRP human calcitonin gene related peptide
  • the h-CGRP has an amino acid sequence of the formula wherein A3 is Asp or Asn, A22 is Val or Met, and A25 is Asn or Ser, and is known to have a various biological proterties [Nature, 308( 19): 746-748 (1984), FEBS Letters, 183 (2): 403 (1985), Neuropeptides, 4 : 425-434 (1984) and Nature, 313 (3): 5456 (1984) ].
  • An object of the present invention is to provide novel h-CGRP derivatives.
  • the present invention provides novel h-CGRP derivatives of the formula wherein R is H or H-Ala-NH- and when A is Asp, B is Asp or Glu, C is Leu and D is Val; when A is Asn and B is Gly, C is Phe and D is Gly; when A is Asn, B is Asp or Glu and C is Leu, D is Gly;and when A is Asn, B is Asp or Glu, and C is Phe, D is Val, or pharmaceutically acceptable salt thereof.
  • a peptice (1) of the present invention can be synthesized by a known conventional process for peptide synthesis.
  • a peptide (1) is synthesized by converting a carboxyl in phenylalanyl in the C-terminal to an amide, condensing successively a protected amino acid and/or a protected lower peptide in the order of amino acid sequence as shown in the formula (1), when R is H, removing the protective group for L-cysteinyl and mercapto in ⁇ -mercaptropropionyl group and the protective group for the functional group in the other side chain by acid hydrolysis, and when R is H-Ala-NH-, removing the protective group for mercapto in L-cysteinyl and theprotective group for the functional group in the other side chain by acid hydrolysis, and oxidizing L-cysteinyl ( or ⁇ -mercaptopropionylgroup ) and mercapto in L-cysteinyl to form a disulfide bridge at a final satge of the condensation reaction.
  • the condensation reaction can be effected by repeating the removal and addition of a protective group and the conden­sation reaction according to the process for conventional peptide synthesis.
  • a protective group for a starting material and intermediates used in the process for the production of a peptide (1) of the present invention is a known protective group in peptide chemistry, for example a protective group which can be easily removed by a known procedure such as hydrolysis, acid decomposition, reduction, aminolysis or hydrazinolysis.
  • the protective groups are well known in the literature of peptide chemistry.
  • Examples of preferred protective groups are butyloxy carbonyl, benzyloxy carbonyl or p-methoxybenzyloxy carbonyl for a ⁇ -amino group, benzyloxy carbonyl or p-chlorobenzyloxy­carbonyl for a side chain amino group such as ⁇ -amino group in lysine, a methyl ester or benzyl ester for an ⁇ -carboxyl group, benzyl ester for a side chain carboxyl group such as the side chain carboxyl in aspartic acid or glutamic acid, benzyl for a hydroxyl group in serine or threonine, mesitylene­-2-sulfonyl or tosyl for the amino group of guanidino in arginine and p-methoxylbenzyl or acetamidomethyl for the mercapto group of cysteine or ⁇ -mercaptopropionic acid.
  • each amino acid and/or lower peptide can be effected by reacting an amino acid or a lower peptide having protcted ⁇ -amino and activated terminal ⁇ -carboxyl, with an amino acid or a lower peptide having free ⁇ -amino and a protected terminal carboxyl group, or alternatively by reacting an amino acid or a lower peptide having activated ⁇ -amino and protected terminal carboxyl with an amino acid or a lower peptide having a protected ⁇ -amino and free terminal carboxyl group.
  • a carboxyl group can be activated by conversion, for example to acid azide, acid anhydride, acid imidazolide or an activated ester such as cyanomethyl ester, p-nitrophenyl esteror N-hydroxysuccinimide ester. Furthermore, it can be activated by using a condensation reagent, for example a carbodiimide such as N, N′-dicyclohexyl-carbodiimide (DCC), N-ethyl-N′-3-dimethylaminopropyl-carbodiimide or N,N′-carbonyl­diimidazole.
  • a condensation reagent for example a carbodiimide such as N, N′-dicyclohexyl-carbodiimide (DCC), N-ethyl-N′-3-dimethylaminopropyl-carbodiimide or N,N′-carbonyl­diimidazole.
  • Examples of prefrred condensation reactions used in the present invention are the azide method, the activated ester method, the mixed anhydride method and the carbodiimide method.
  • the condensation reaction it is preferred to avoid or at least to minimize the racemization reaction; and preferred such processes are the azide method, the activated ester method, the Wunsch Method [Z. Naturforsch., 21b, 426 (1966)] or the Geiger method [Chem. Ber., 103, 788 (1970)].
  • a peptide (1) can be synthesized in any procedure : however, it is preferable to construct an amino acid sequence by connecting amino acid and/or lower peptide in order from the C-terminal.
  • a peptide (1) wherein R is H can be obtaianed by removing the protective groups in the protected peptide chain, namely ⁇ -mercaptopropionyl pentatriaconta-peptideamide having protected ⁇ -amino, side chain carboxyl, hydroxyl, guanidino and mercapto groups.
  • These protective groups are preferably removed by onestep removal with acid hydrolysis using for example trifluoro-methane sulfonic acid or anhydrous hydrogen fluoride to obtain ⁇ -mercaptopropionyl pentatriaconta-peptideamide having free mercapto group.
  • a peptide (1) wherein R is H-Ala-NH- can be obtained by removing the protective groups in the protected peptide chain, namely heptatriaconta-peptideamide having protected ⁇ -amino, side chain carboxyl, hydroxyl, guanidino and mercapto groups. These protective groups are preferably removed by the same way as above to obtain heptatriaconta-­peptideamide having free mercapto group.
  • an inner molecular disulfide linkage is formed by oxidation to obtain the peptide (1).
  • Disulfide linkage can be effected generally by oxidation with oxygen in water, diiodo-ethane in an organic solvent, iodine in glacial acetic acid or potassium ferricyanide in water.
  • a solid phase peptide synthesis method can be used in part or in total as the process of peptide (1) synthesis.
  • peptide fragment (3-37) [hereinafter peptide of amino acid sequence constituted of amino acids from Nos. 3 to 37 is abbreviated as peptide fragment (3-37) or peptide (3.37)] is synthesized by a solid phase method, and the ⁇ -amino group in the said peptide is acylatd with ⁇ -mercaptopropionic acid to obtain a protected pentatriaconta­-peptide-bound resin or a protected heptatriaconta-peptide-bound resin.
  • a peptide (1) can be obtained by constructing an inner molecule disulfide bond as set forth in the process by liquid phase synthesis hereinabove.
  • resin used in the solid phase method are conventional resins such as benzhydrylamine resin or p-methyl-benzhydrylamine resin.
  • a resin with the desired functional equivalent or cross-linkage can be synthesized but is also commercially available.
  • an amino acid is condensed in the resin, in the order of amino acid sequence of formula (1), from C-terminal amino acid to the third number of amino acid (amino acid No. 3) or from C-terminal amino acid to the 1st number of amino acid (amino acid No.1), and in the case of a peptide wherein R is H, it is acylated with ⁇ -mercaptopropionic acid at the condensation to the third amino acid.
  • a functional group in the amino acid isprotected by a known method. Examples of protective groups are set forth hereinbefore.
  • a resin in a reaction vessel is swelled by adding dichloromethane, chloroform, dimethylformamide, benzene or a solvent for swelling the resin, in a ratio of 2-20 ml solvent per 1 g resin.
  • 1-6 equivalents of t-butyloxycarbonyl (hereinafter designated Boc-) amino acid per 1 equivalent of amino group in the resin are first reacted with DCC, and the obtained acid anhydride, which is separated from a by-product dicyclohexylurea (hereinafter designatd DCU), is added to the resin hereinabove.
  • the amount of condensation agent (DCC) is 0.5-3 equivalents per 1 equivalent of Boc-amino acid. The reaction proceeds generally for 5-60 minutes.
  • the coupling amount of amino acid or peptide can be determined according to a conventional method [T. Fairwell et al., Biochemistry, 22 : 2691 (1983) ] by checking the amount of Boc-amino acid upon sampling the Boc-amino acid-resin or Boc-peptide-resin obtained in each process.
  • the protective group for the ⁇ -amino group, Boc is removed by an acid such as trifluoroacetic acid and the condensation reaction is performed.
  • An automatic solid phase synthesizer can be used; however, a manual procedure can also be used.
  • the entire operation is preferably performed under a nitrogen gas atmosphere.
  • a peptide fragment (3-37) bound to resin is acylated with ⁇ -mercaptopropionic acid in the final step to obtain a ⁇ -mercaptopropionyl-protected pentatriaconta peptide-amide-­bound resin.
  • the thus-obtained protected pentatriaconta peptideamide-­bound resin or protected heptatriaconta peptide amide-bound resin is, as previously described, treated with anhydrous hydrogen fluoride to remove the protective group and resin in one-step, whereby ⁇ -mercaptopropionyl pentatriaconta peptide-amide having a free mercapto group or heptatriaconta peptide-amide having a free mercapto group can be obtained.
  • a peptide (1) can be obtained by forming intra molecular disulfide bonds in the above peptide-amide. Isolation and purification:
  • the thus-obtained peptide (1) can be purified by aurification methods which are well known in peptide or protein chemistry.
  • aurification methods which are well known in peptide or protein chemistry.
  • a gel-filtration method can be carried out using Sephadex G-25, Sephadex G-50 or Sephadex LH-20 (trade names), or ion-exchange chromatography using carboxy methyl cellulose, or another resin, or HPLC can be used.
  • a peptide (1) of the present invention can be obtained according to the process in the form of free base or salt.
  • a salt with a known organic acid such as acetic acid, citric acid, malic acid or tartaric acid can be prepared.
  • Serum calcium and serum phosphate reducing activities Serum calcium and serum phosphate reducing activities:
  • the peptide (1) of the present invention and known h-CGRP (each 80 ⁇ g) dissolved in citrate buffer, pH.6.5, containing 0.1% bovine serum albumin (hereinafter designated dissolving medium) (1 ml) were administered intravenously into the tail vein of Wistar rats, body weight 80-90 g, 5-6 rats in one group, at 80 ⁇ g /kg. After 30 and 60 mins. of administration, blood samples were collected from the abdominal descending aorta. The serum calcium concentration was measusred by atomic adsorption spectrophotometry. Serum phosphate was measured by a method according to Goldenberg et al. [Clin. Chem., 12: 872-882 (1966)].
  • Figure 1 is a graph showing the rat serum calcium reducing effect of h-CGRP and peptide (1) of the present invention
  • Figure 2 is a graph showing the rat serum inorganic phosphate reducing effect of h-CGRP and peptide (1) of the present invention.
  • the concentrations of serum calcium and phosphate were reduced by more than 20-30% in desalanyl-deamino- [Asp14 ] h-CGRP(2-37), 80 ⁇ g /kg, administered group [ - ⁇ - ] , [Asp14] h-CGRP(1-37) [ - ⁇ - ] , [Asn3,Phe15,Gly23] h-CGRP(1-37) [ - ⁇ - ] , [Asn3,Asp14, Gly23 ] h-CGRP(1-37) [ - ⁇ - ] , and [Asn3,Asp14,Phe15 ] h-CGRP(1-37) [ - ⁇ - ] as compared with control group (dissolving medium administered group) [ - X - ] and these activities were observed to continue after 2 hours. These activities were stronger and those of h-CGRP [ - ⁇ - ]
  • the peptide (1) of the present invention has stronger serum calcium reducing activity and serum phosphate reducing activity as comparaed with known h-CGRP. Furhtermore, it has longer-lasting activity as compared with known h-CGRP. Moreover, it is useful for treatment of calcium metabolic disorders, cardiac disease and ulcers, or for the improvement of cerebral circulation.
  • This powder (200 mg) was dissolved in 50 mM Na2HPO4 buffer (pH 7.5, 15 ml) containing 8 Murea and 5mM dithiothreitol, and stirred for 1 hour, then diluted with 50 mM Na2HPO4 buffer (pH 7.5, 1300 ml), thereafter 20 mM K3Fe(CN)6 aqueous solution (9 ml) was added thereto.
  • Residual powder 200 mg was treated by the same way to obtain furhter white poentrée (60 mg).
  • Combined powder was charged on a column (2.5 x 25 cm) of Cm-Toyopearl 650 M (trademark), and eluted by linear gradient elution with 0.1 N aq. acetic acid (700 ml) ⁇ 0.4 M aq. ammonium acetate (pH 5, 700 ml).
  • Fractions (each 10 ml) Nos. 105-123 were collected and freeze dried to obtain white powder.
  • Buffer 0.1% TFA-acetonitrile (a gradient elution with acetonitrile concentration from 28 to 32% for 20 minutes)
  • Solid phase peptide synthesizer 430-A peptide synthesizer Applied Biosystems Inc.
  • MBHA-resin (Applied Biosystems Inc., amino group: 0.48mM/g) (1.04 g) in a raction vessel for solid phase peptide synthesis was treated with DCM (8 ml) (4 times, each 1 min.), DCM solution (8 ml) containing 60% TFA (20 min.), DCM (4 ml) (3 times, each 15 sec.), DMF solution (3 ml) containing DIEA (1 ml) (2 times, each 1 min.) and DMF (8 ml) (6 times, each 40 sec.),in this order, under a nitrogen gas atmosphere with stirring. The material was filtered after each treatment.
  • Boc-Phe-MBHA-resin hereinabove was washed 4 times with DCM (8 ml, each 1 min.) in the reaction vessel and filtered. 40% DCM solution (8 ml) conataining 60% TFA was added thereto and stirred for 20 min. to remove Boc. The thus-obtained resin was washed 3 times with DCM (4 ml, each 15 sec.), 2 times with DMF solution (3 ml) containing DIEA (1 ml) (each 1 min.) and 6 times with DMF (8 ml, each 40 sec.), in this order, and filtered.
  • amino acids (sequence from Nos. 1 to 35) were subjected to a coupling reaction and at a final step of the raction Boc was removed by DCM solution containing 60% TFA, then washed with DCM, DIEA and DMF to obtain protected [Asn3, Phe15,Gly23 ] h-CGRP(1-37)-MBHA-resin.
  • the protected amino acids used in the process are as follows:
  • the powder (152 mg) was dissolved in 50 mM Na2HPO4 buffer (pH 7.5, 10 ml) containing 8 M urea and 5 mM dithiothreitol, and stirred for 1 hour, then diluted with 50 mM Na2HPO4 buffer (pH 7.5, 1125 ml), thereafter 20 mM K3Fe(CN)6 aqueous solution (8 ml) was added thereto.
  • Residual powder (154 mg) was treated by the same way to obtain furhter white powder (40 mg). Combined powder was charged on a column (2.5 x 20 cm) of CM-Toyopearl 650 M (trademark), and eluted by linear gradient elution with distilled water (700 ml) ⁇ 0.4 M aq. ammonium acetate (pH 5,700 ml). Fractions (each 10 ml) Nos. 108-116 were collected and freeze dried to obtain a white powder. The thus obtained white powder dissolved in 0.1 M acetic acid was charged on a column of Sephadex G-25 Fine (trade name) (2.6x 90 cm) and eluted with 0.1 M acetic acid.
  • Sephadex G-25 Fine trade name
  • Buffer 0.1% TFA-acetonitrile (a gradient elution with acetonitrile concentration from 28 to 32% for 25 minutes)
  • Arg is analysed by citrulline.
  • the protected amino acids used in the process are as follows:
  • This powder (150 mg) was dissolved in 50 mM Na2HPO4 buffer (pH 7.5, 10 ml) containing 8 M urea and 5 mM dithiothreitol, and stirred for 1 hour at room temperature, then diluted with 50 mM Na2HPO4 buffer (pH 7.5, 1125 ml), there-after 20 mM K3Fe(CN)6 aqueous solution (8 ml) was added thereto.
  • Buffer 0.1% TFA-acetonitrile (a gradient elution with acetonitrile concentration from 30 to 33% for 20 minutes)
  • Arg is analysed by citrulline.
  • the protected amino acids used in the process are as follows:
  • This powder was dissolved in 50 mM Na2HPO4 buffer (pH 7.5, 20 ml) containing 8 M urea and 5mM dithiothreitol, and stirred for 1 hour, then diluted with 50 mM Na2HPO4 buffer (pH 7.5, 2000 ml), thereafter 20 mM K3Fe(CN)6 aqueous solution (10 ml) was added thereto.
  • Buffer 0.1% TFA-acetonitrile (a gradient elution with acetonitrile concentration from 29 to 34% for 30 minutes).
  • Arg is analysed by citrulline.
  • the protected amino acids used in the process are as follows:
  • This powder was dissolved in 50 mM Na2HPO4 buffer (pH 7.5, 20 ml) containing 8 M urea and 5 mM di­thiothreitol, and stirred at room temperature for 1 hour, then diluted with 50 mM Na2HPO4 buffer (pH 7.5, 2000 ml), thereafter 20 mM K3Fe(CN)6 aqueous solution (12 ml) was added thereto.
  • Buffer 0.1% TFA-acetonitrile (a gradient elution with acetonitrile concentration from 31.5 to 32.5% for 30 minutes
  • Amino acids (sequence from Nos. 3 to 37) were subjected to a coupling reaction by the solid phase synthesis as same as of in Example 1 and the peptide was acylated with MBzl- ⁇ -­mercaptopropionic acid at the final stage of reaction to obtain protected-desalanyl-deamino [Asp14] h-CGRP (2-37)-MBHA-resin.
  • the protected amino acids used in the process are as follows:

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EP88306600A 1987-07-22 1988-07-19 Dérivés de gènes peptides de calcitonine apparentés Expired - Lifetime EP0300737B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP62182891A JPS6426598A (en) 1987-07-22 1987-07-22 Calcitonin gene related peptide derivative
JP182891/87 1987-07-22

Publications (3)

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EP0300737A2 true EP0300737A2 (fr) 1989-01-25
EP0300737A3 EP0300737A3 (en) 1990-02-28
EP0300737B1 EP0300737B1 (fr) 1993-04-14

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EP88306600A Expired - Lifetime EP0300737B1 (fr) 1987-07-22 1988-07-19 Dérivés de gènes peptides de calcitonine apparentés

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US (1) US4992530A (fr)
EP (1) EP0300737B1 (fr)
JP (1) JPS6426598A (fr)
DE (1) DE3880226T2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0385712A3 (fr) * 1989-02-28 1991-02-06 Asahi Kasei Kogyo Kabushiki Kaisha Peptide utilisable dans la préparation d'une composition en vue de la prévention ou du traitement d'états susceptibles d'être traités par un inhibiteur de l'agrégation plaquettaire
EP0672419A4 (fr) * 1991-12-12 1995-06-22 Asahi Chemical Ind Regulateur de la pression sanguine.

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992015317A1 (fr) * 1991-03-08 1992-09-17 Amylin Pharmaceuticals, Inc. Preparation synthetique d'amyline et d'analogues d'amyline
HU222249B1 (hu) * 1991-03-08 2003-05-28 Amylin Pharmaceuticals Inc. Eljárás amilin agonista peptidszármazékok és ezeket tartalmazó gyógyszerkészítmények előállítására
US5567679A (en) * 1993-12-13 1996-10-22 Daly; Theodore J. Use of CGRP in treating alopecia
CA2292902C (fr) * 1999-12-24 2012-12-18 Alain Cadieux Utilisation de peptide calcitonine lie aux genes dans la prevention et le soulagement de l'asthme et d'affections bronchospasmodiques connexes

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62129297A (ja) * 1985-08-09 1987-06-11 Toyo Jozo Co Ltd カルシトニン遺伝子関連ペプチド誘導体

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0385712A3 (fr) * 1989-02-28 1991-02-06 Asahi Kasei Kogyo Kabushiki Kaisha Peptide utilisable dans la préparation d'une composition en vue de la prévention ou du traitement d'états susceptibles d'être traités par un inhibiteur de l'agrégation plaquettaire
EP0672419A4 (fr) * 1991-12-12 1995-06-22 Asahi Chemical Ind Regulateur de la pression sanguine.

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Publication number Publication date
US4992530A (en) 1991-02-12
DE3880226T2 (de) 1993-07-29
EP0300737B1 (fr) 1993-04-14
JPS6426598A (en) 1989-01-27
DE3880226D1 (de) 1993-05-19
EP0300737A3 (en) 1990-02-28

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